Renal calculous disease remains a common disorder in this country, and some studies even suggest that stone disease is on the rise. In 1950, only 0.95 per one thousand Americans were estimated as having the disease. By 1984, this number had risen to 1.64 per one thousand Americans. Boyce, W. H. [1979] "Epidemiology of Lithiasis in the United States," XVIIIth C. M. Congress of the International Society of Urology, Paris, Kongressbericht, Tome 1, pp. 79-86. Indeed, Sierakowski et al. (Sierakowski, R., B. Finlayson, R. R. Landes, C. D. Finlayson, N. Sierakowski [1978] Invest. Urol. 16:438-441) estimated that about 12% of the U.S. populace will suffer from stone disease at least once in their lifetime. The most prevalent type of renal stone disease is of a calcareous and idiopathic nature, occurring mostly in white males. Geographic and dietary factors can affect incidence.
Kidney stone disease arising from pathological calcium oxalate biomineralization accounts for hospitalization and surgery or extensive outpatient extracorporeal shock-wave lithotripsy treatment of approximately 500,000 U.S. residents annually. The per annum cost (exclusive of occupational time lost during treatment and recuperation) has been estimated at $3 billion. Davis et al. (Davis, G. K., N. B. Cummings, B. Finlayson, J. L. Meyer, M. J. V. Smith "Urolithiasis," in Geochemistry and the Environment, Natl. Acad. Sci., Washington, pp. 133-138) put the number of lost working days at nearly 15,000,000 annually in this country alone, which translates to around 56,000 person-years of productivity lost each year. An even more telling expression of the economic impact is that a work force of 56,000 corresponds to the productivity of an entire city of about 130,000 to 150,000.
Unlike normal biomineralization processes (e.g., bone and tooth formation), calcium oxalate urolithiasis is a pathological process (Thomas, Jr., W. C., [1976] Renal Calculi: A Guide to Management, Charles C. Thomas, Publisher, Springfield, Ill., 177 pp.). Crystallization within the urinary tract occurs opportunistically and quite freely such that formation of smaller crystallites is a normal renal function for eliminating calcareous stone salts. Abnormal conditions presumably result from uncontrolled crystal agglomeration and/or cellular attachment/retention of crystals. Stone disease arises when crystallite attachment is not blocked within the urinary tract. Consequently, further biomineralization and accretion of other cell debris and solutes create flow-obstructing kidney stones. Although certain factors, e.g., uncontrolled biosynthesis of oxalate (hyperoxaluria), elevated phosphate levels (phosphaturia), and excessive dietary intake of oxalate-rich foods can exacerbate stone formation, it remains an idiopathic disease.
Methods for detecting kidney stone formation or treating kidney stone disease have been described, but are quite different from the subject invention. For example, U.S. Pat. No. 5,137,722 describes an extract and pharmaceutical composition for treatment of calcium oxalate stone disease. The extract is purified from the plant Eriobotrya japonica. The extract does not consist of any citrate-containing compounds.
U.S. Pat. No. 4,399,003 describes a method and kit for diagnosing a patient's proneness to develop calcium oxalate-type kidney stones. The method comprises measuring the rate of decrease of calcium ion concentration in the patient's urine sample as compared to a reference standard of normal urine. This method differs substantially from the diagnostic method described hereinbelow.
U.S. Pat. No. 4,888,182 also describes methods and compositions for the treatment and prophylaxis of calcium renal stones. By contrast, the subject invention comprises a novel compound, clearly distinguishable from the citrate salt and methods of using that salt as described in the '182 patent.
Except for a small fraction of stone-formers (e.g., individuals with primary hyperoxaluria, those with renal tubular acidosis, and others having chronic hypercalcemic disorders), there has been no clearly defined criteria that characterize the much larger group of idiopathic kidney stone-formers.
A few other potential diagnostic tools for discerning urolithiasis have been described. Illustrative are the work of Zhmurov (Zhmurov, V. A. [1991] Urol. Nefrol-Moscow May-June (3):12-15), who found altered phospholipid composition in the urine of stone-formers, and Azoury et al. ([1990] Urolog. Res. 18:7-11) who described the use of nuclear magnetic resonance proton-relaxation-rates (PRR) to distinguish healthy and stone-former urine samples.
The techniques described either by Zhmurov et al. or Azoury et al. have not been instituted as a commercial diagnostic measure. The obvious disadvantages of analyzing changes in patterns of phospholipid composition and the unavailability of nuclear magnetic resonance instrumentation in clinical laboratories may be contributing factors to the absence of commercial application of these approaches. More fundamentally, the changes reported by Zhmurov et al. and Azoury et al. may relate to secondary pathophysiologic responses to the presence of kidney stones, and they may not be generally applicable prior to the occurrence of stone disease.
The type of calculus evidenced in any particular patient is due primarily to a urinary deficiency of inhibitors normally present to help suppress crystal formation (Schrier, E. E., K. E. Lee, J. L. Rubin, P. G. Werness, L. H. Smith [1979] "Macromolecular Inhibitors of Calcium Oxalate Crystal Growth and Aggregation in Urine," In Oxalate in Human Biochemistry and Clinical Pathology (G. A. Rose et al., eds.), London, The Welcome Foundation, pp. 22-61; Thomas, Jr., W. C. [1988] Md. Med. J. 37:861-862; Coe, F. L., Y. Nakagawa, J. H. Parks [1991] Am. J. Kidney Disease 17:407-413). However, epidemiological studies of certain substances, e.g., citrate, phosphate, pyrophosphate, glycosaminoglycans, nephrocalcin, Tamm-Horsfall proteins, and uropontin, showed that none of these substances can be used as an unambiguous, single-determinant calcareous stone disease marker.
Accordingly, the development of prospective diagnostic techniques to identify those patients who are predisposed to developing kidney stones is needed to provide a means for mitigating these costs through the exercise of preventative practices by those predisposed patients. Therefore, the discovery of an unambiguous marker as described hereinbelow is a substantial contribution to the art.